Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the US and the world. The most recent estimates indicate approximately 50,000 people will die of the disease in the US in 2015 alone. The central challenge in the design and development of drugs to treat CRC has been the validation of novel drug targets and the generation of new therapies aimed at those targets. Although PTP4A3 is currently among the most consistently up-regulated proteins seen in colorectal tumors, it suffers from an incomplete understanding of its substrate(s) and of its participation in tumor formation and progression. There is considerable evidence linking protein-tyrosine phosphatase 4A3 (PTP4A3) to colorectal cancer in humans; moreover, animal models of the disease indicate that PTP4A3 may be a viable target in the treatment of CRC. The proposed study will address several outstanding questions with regard to the role of PTP4A3 in the context of CRC and reveal new mechanistic insights. The availability of mice lacking functional PTP4A3 in addition to non-malignant and colorectal tumor cells from these mice provide, for the first time, critical reagents that enable the investigation, in a definitive manner, of what this protein does and what processes it controls. The first aim will employ both malignant and non-malignant cells lacking functional PTP4A3, allowing the re- introduction of wild-type PTP4A3 and domain specific mutants to determine the functional domain(s) necessary for the control of cellular migration and invasion by PTP4A3. The second aim will use Ptp4A3-null mice and isolated colorectal tumor cells in combination with their wild-type counter parts to establish the unexplored importance of PTP4A3 expression in non-malignant cells during tumor formation and progression. Given the clear unmet need for novel approaches to treating CRC, the findings of this study have the potential to greatly advance the development of new therapeutic strategies targeting PTP4A3. Supplementing the research component of the proposal with didactic coursework, engagement in research meetings and seminars, and participation in scientific conferences will ensure an understanding of current concepts and techniques, constant feedback regarding the project's results and progress, and enhanced exposure to more translational work. Collectively, the research and training plan will provide a strong foundation upon which to build a career as a productive, independent cancer researcher.